Inhibitors of p38-a kinase

ABSTRACT

The invention is directed to methods for treating conditions mediated by by P38α kinase using compounds of the formula                    
     wherein Ar 1  and Ph are limited to specific embodiments or wherein the compound of formula (3) is a compound set forth in FIGS.  1 A- 1 T.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.09/385,494, filed Aug. 27, 1999, now U.S. Pat. No. 6,410,540 thecontents of which are incorporated herein by reference. This applicationclaims priority under 35 U.S.C. § 119(e) to provisional application Ser.No. 60/185,571 filed Feb. 28, 2000, the contents of which areincorporated herein by reference.

TECHNICAL FIELD

The invention is directed to compounds that are useful in treatinginflammation and cardiac conditions and that contain N-containingheterocycles such as piperazine or piperidine moieties coupled to phenyland other aryl groups. More particularly, the invention concernscompounds of this type as well as methods to treat proinflammatory andheart and kidney conditions using these and other compounds.

BACKGROUND ART

A large number of chronic and acute conditions have been recognized tobe associated with perturbation of the inflammatory response. A largenumber of cytokines participate in this response, including IL-1, IL-6,IL-8 and TNF. It appears that the activity of these cytokines in theregulation of inflammation rely at least in part on the activation of anenzyme on the cell signaling pathway, a member of the MAP kinase familygenerally known as p38 and alternatively known as CSBP and RK. Thiskinase is activated by dual phosphorylation after stimulation byphysiochemical stress, treatment with lipopolysaccharides or withproinflammatory cytokines such as IL-I and TNF. Therefore, inhibitors ofthe kinase activity of p38 are useful anti-inflammatory agents.

PCT applications WO98/06715, WO98/07425, WO98/28292 and WO 96/40143, allof which are incorporated herein by reference, describe the relationshipof p38 kinase inhibitors with various disease states. As mentioned inthese applications, inhibitors of p38 kinase are useful in treating avariety of diseases associated with chronic inflammation. Theseapplications list rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, sepsis,septic shock, endotoxic shock, Gram-negative sepsis, toxic shocksyndrome, asthma, adult respiratory distress syndrome, stroke,reperfusion injury, CNS injuries such as neural trauma and ischemia,psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatorydisease, silicosis, pulmonary sarcosis, bone resorption diseases such asosteoporosis, graft-versus-host reaction, Crohn's Disease, ulcerativecolitis including inflammatory bowel disease (IBD) and pyresis.

The above-referenced PCT applications disclose compounds which are p38kinase inhibitors said to be useful in treating these disease states.These compounds are either imidazoles or are indoles substituted at the3- or 4-position with a piperazine or piperidine ring linked through acarboxamide linkage. Additional compounds which are conjugates ofpiperazines with indoles are described as insecticides in WO97/26252,also incorporated herein by reference.

U.S. Pat. No. 5,719,135 describes tyrosine kinase inhibitors containingpiperidine or piperazine rings linked through a methylene at position 1of piperidine to various aromatic systems which must further contain a γlactam fused to a pyridine ring. Similar compounds are described in U.S.Pat. No. 5,663,346 and in WO96/22976. Other cyclic tyrosine kinaseinhibitors are described in PCT application WO95/06032. In addition,WO94/20062 describes balanoids as protein kinase C inhibitors. Thebalanoid compounds contain multiple aromatic systems which include atleast a ring containing at least seven members. Some of the compoundsuseful in the method of the present invention are known compounds.

Additional compounds which contain piperidine or piperazine linked to anindole, benzimidazole, or benztriazole ring system are disclosed in PCTpublication WO99/61426 published Dec. 2, 1999; PCT publicationWO00/59904 published Oct. 12, 2000, and PCT publication WO00/71535published Nov. 30, 2000, the contents of all of which are incorporatedherein by reference. Related compounds to those described herein arealso set forth in PCT publication WO00/12074 published Mar. 9, 2000 andincorporated herein by reference.

DISCLOSURE OF THE INVENTION

The invention is directed to methods of treating inflammation generally,including specific conditions such as those described in the Backgroundsection above. The compounds of the invention have been found to inhibitp38 kinase and are thus useful in treating diseases mediated by thisenzyme. These compounds also inhibit p38α preferentially as compared totheir inhibition of p38β as is further discussed below.

The compounds useful in the invention are of the formula

and the pharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof,

wherein

Z is N or CR¹, R¹ is a noninterfering substituent,

each of X¹ and X² is a linker,

Ar¹ and Ar² are identical or different, and represent optionallysubstituted C1-C20 hydrocarbyl residues wherein at least one of Ar¹ andAr² is an optionally substituted aryl group, with the proviso that whenX² is CH₂ or an isostere thereof, X¹ is CO or an isostere thereof, andAr² is optionally substituted phenyl, Ar¹ is other than an optionallysubstituted indolyl, benzimidazolyl or benzotriazolyl substituent, andwherein said optionally substituted phenyl is not an optionallysubstituted indolyl, benzimidazolyl, or benzotriazolyl,

Y is a noninterfering substituent, wherein n is an integer from 0-4, and

wherein m is an integer from 0-4 and 1 is an integer from 0-3.

Preferably, the compounds useful in the invention are of the formula

and the pharmaceutically acceptable salts thereof,

wherein Ar¹ is optionally substituted furanyl, thiophenyl, phenyl systemhaving 0, 1, or 2 heterocyclic N atoms or naphthyl system having 0, 1, 2or 3 heterocyclic N atoms;

X¹ is CO or an isostere thereof;

Y is optionally substituted alkyl (1-6C), optionally substituted aryl(6-10C), or optionally substituted arylalkyl (7-11C);

n is 0 or 1;

Z is CH or N;

X² is CH₂ or an isostere thereof; and

Ph is optionally substituted phenyl.

The optional substituents on the aryl moieties (including phenyl)include halo, nitro, optionally substituted alkyl (1-6C) or alkenyl(1-6C), CN, guanidino or CF₃, as well as RCO, COOR, CONR₂,SO₂NR_(2,)—OOCR, —NROCR, —NROCOR, NR₂, OR or SR, wherein R is H or alkyl(1-6C), as well as substitution by phenyl, itself optionally substitutedby the foregoing substituents. Any two substituents may form a 5-7membered carbocyclic or heterocyclic ring subject to the proviso.

Thus, in one aspect, the invention is directed to compounds of theformulas set forth above and to pharmaceutical compositions containingthem. In other aspects, the invention is directed to methods oftreatment and preparation of medicaments using compounds of the formulaset forth above. The invention is also directed to uses of specificclasses of compounds within the genus of formula (1). In particular, theinvention is related to compounds of formula (3)

In other aspects, the invention is directed to methods to produce thecompounds useful in the invention.

In particular, the invention is directed to the use of compounds offormula (3) to prepare a medicament for treatment of conditions mediatedby p38α kinase or to methods of treatment of such conditions wherein thesubstituents in formula (3) are defined in the alternative as follows:

1. In formula (3), Ar¹ is a furanyl ring system optionally substitutedby noninterfering substituents other than phenyl;

X¹ is CO or an isostere thereof;

Z is N or CH;

X is CH₂ or an isostere thereof; and

Ph is optionally substituted phenyl.

2. In formula (3), Ar¹ is a thiophene ring system optionally substitutedby a noninterfering substituent, and not fused to an additional ring;

X¹ is CO or an isostere thereof;

Z is N or CH;

X² is CH₂ or an isostere thereof; and

Ph is optionally substituted phenyl.

3. In formula (3), Ar¹ is an optionally substituted aryl group otherthan optionally substituted indolyl, benzimidazolyl, or benzotriazolyl;

X¹ is CO or an isostere thereof;

Z is N or CH;

X² is CH₂ or an isostere thereof; and

Ph represents optionally substituted phenyl

wherein at least one of Ar¹ and Ph is substituted by at least onesubstituent comprising a saturated ring system optionally containing 1-2N atoms and/or 1-2 O atoms.

4. The compound of formula (3) is a compound illustrated in FIGS. 1A-1I.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1T show structures of additional compounds of the invention.

MODES OF CARRYING OUT THE INVENTION

The compounds of formula (1) set forth above are defined by the natureof the substituents on the heterocycloalkyl ring in the center of theformula. Piperazine or piperidine rings are preferred and piperidinerings are more preferred. The central piperazine or piperidine ring canbe expanded or contracted using —CH₂ groups so that it includes from 4members up to 11 members. The substitution on this ring is on the N or Zpositions only. Although not bound by this theory, the function of thecentral heterocycloalkyl group is apparently to space the Ar² group,which is generally hydrophobic, from the Ar¹ group, which is preferablybut not necessarily hydrophilic.

The central heterocycloalkyl ring can include from 1-2 N. If the ringcontains only 1 N then Z is a —CR¹ wherein R¹ is a noninterferingsubstituent. Preferably, R¹ is alkyl, alkoxy, aryl, arylalkyl, aryloxy,heteroaryl, halogen, acyl, carboxy, or hydroxy. More preferably, R¹ ishydroxy, alkyl, or alkoxy.

The linker that couples the central heterocycloalkyl ring and the Ar¹and Ar² groups on either end of the molecule are preferably saturated orunsaturated alkylene optionally containing 1-4 carbonyl, 1-4 SO₂, and/or1-3 heteroatoms, including a linker which is CO, SO₂, SO or contains aheteroatom, and optionally substituted with a substituent selected fromthe group consisting of halo, alkyl, alkoxy, cycloalkyl, aryl, aryloxy,arylalkyl, haloalkyl, polyhaloalkyl, haloalkoxy, polyhaloalkoxy,cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, heteroarylalkyl,heteroaryloxy, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio,heteroarylsulfinyl, heteroarylsulfonyl, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, alkoxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, acyl, aminocarbonyl,arylcarbonyl, heteroarylcarbonyl, cyano, carboxy, hydroxy, tetrazolyl,imidazole, oxazole, triazole, and —SOR wherein R is hydroxy, alkyl,aryl, alkoxy, aryloxy, cycloalkyl, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylalkoxy or cycloheteroalkylalkoxy.

Preferably the linker is a methylene group, a carbonyl group, amethylene group coupled to a carbonyl group, a methylene group having amethyl substituent or a methylene group containing an optionallysubstituted phenyl group. The alkylene group is C1-C8, and preferablyC1-C4, and more preferably C1. Preferably, haloalkyl or polyhaloalkylgroups are CF₃ or CF₃CH₂ and haloalkoxy or polyhaloalkoxy groups areCF₃O or CF₃CH₂O.

Ar¹ or Ar² is an aryl group which is the residue of an aromatichydrocarbon containing one or more rings optionally including one ormore heteroatoms, selected from the group of O, N and S. Preferably thearyl group has 6-12 carbon atoms and up to 3 heteroatoms, and morepreferably the aryl group has 6-8 carbon atoms and 1 or 2 heteroatoms.More preferably, the aryl group is a saturated or unsaturated 5-7membered heterocycle and even more preferably a saturated or unsaturated5-6 membered heterocycle. Most preferably, the aryl group is phenyl orresidues of an optionally benzo-fused heterocycle containing up to 3heteroatoms selected from S, N and O. The most preferable aryl groupsare indolyl, isoquinolyl, quinolyl, benzimidazolyl, benzotriazolyl,benzothiazolyl, benzofuranyl, pyridyl, thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. When thelinker is not CO or an isostere thereof, Ar¹ or Ar² is most preferablyindolyl, benzimidazolyl or benzotriazolyl.

Ar¹ and Ar² and/or other aryl substituents are optionally substitutedwith substituents including one or more of halo, alkyl, alkoxy,cycloalkyl, aryl, aryloxy, arylalkyl, haloalkyl, polyhaloalkyl,haloalkoxy, polyhaloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl,heteroaryl, heteroarylalkyl, heteroaryloxy, arylthio, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, acyl,aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, cyano, carboxy,hydroxy, tetrazolyl, imidazole, oxazole, triazole, and —SOR wherein R ishydroxy, alkyl, aryl, alkoxy, aryloxy, cycloalkyl, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroarylalkoxy orcycloheteroalkylalkoxy. Preferably the substituents include halo,alkoxy, alkoxyaryl, aminoalkyl, aminoaryl, and substituted aryl. Mostpreferably Ar¹ and Ar² include at least one halo, alkoxy, orN-containing substituent.

Y is selected from the group consisting of H, optionally substitutedalkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl, cycloheteroalkyl,heteroaryl, halogen, alkylaminocarbonyl, arlyaminocarbonyl,heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl,arylcarbonyl, heteroarylcarbonyl, cyano, amino, and alkylamino.Preferred groups are hydroxy, alkyl and carbonyl.

The compounds of formula (2) set forth above are defined by the natureof the substituents on the piperazine or piperidine ring. Piperidinerings are preferred.

In formula (2), Ar¹ is optionally substituted furanyl, thiophenyl,optionally substituted phenyl systems having 0, 1, or 2 heterocyclic Natoms or naphthyl systems having 0, 1, 2 or 3 heterocyclic N atoms. Thenature of the substituents and the preferred substituents are discussedbelow.

X¹ is CO or an isostere thereof. Thus, in addition to CO, X¹ may be CH₂,SO, SO₂, or CHOH. CO is preferred.

Z is CH or N.

X² is CH₂ or an isostere thereof.

The aryl moieties represented by Ar¹ and Ph in formula (2) mayoptionally be substituted by substituents including straight or branchedchain alkyl (1-6C), straight or branched chain alkenyl (2-6C), halo,RCO, COOR, CONR₂, SO₂NR₂, —OOCR, —NROCR, —NROCOR, OR, SR, NR₂, NO₂, CN,or CF₃, wherein R is H or straight or branched chain alkyl (1-6C).Phenyl moieties may also be substituted with an additional phenylresidue, preferably at the 4-position. Any two substituents may form a5-7 membered carbocyclic or heterocyclic ring subject to the proviso.The additional phenyl residue may itself be substituted with thesubstituents set forth above. The additional phenyl may be substitutedin all five positions, but preferably less, preferably in 1-2 positionsor not at all.

Preferred substituents include halo, alkyl (1-6C), OR, SR and NR₂, morepreferably halo, OR and alkyl (1-4C), most preferably halo and OCH₃. Thesubstituents on the phenyl moiety as an embodiment of Ar¹ or on Ph mayoccupy all five available positions, preferably 1-2 positions or thephenyl is unsubstituted. If Ar¹ comprises a pyridyl residue, only 4positions are available; preferably only 1-2 positions are substitutedor preferably the pyridyl is unsubstituted. If Ar¹ comprises furanyl orthiophenyl, only 3 positions are available; preferred numbers ofsubstitutions in this case are 1 or 0.

n may be 0 or 1, and is preferably 0. However, when n is 1, Y is presentand may be alkyl, arylalkyl or aryl, all of which may optionally besubstituted by the substituents set forth above. Preferred embodimentsof Y include unsubstituted alkyl (1-6C) and unsubstituted arylalkyl(7-11C), most preferably unsubstituted lower alkyl (1-4C).

In one group of compounds of formula (3), Ar¹ is a furanyl ring systemoptionally substituted by noninterfering substituents other than phenyl.These noninterfering substituents may include alkyl, alkoxy, cycloalkyl,cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy,aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, CF₃, cyano, amino andalkylamino.

Preferred substituents are alkyl, halo, CF₃, alkoxy, and cycloalkyl.Embodiments containing 0, 1 and 2 substituents are preferred, inparticular embodiments with 0 or 1 substituents.

In a second embodiment of the compounds of formula (3), Ar¹ is athiophene ring system containing optional substitutions withnoninterfering substituents. The thiophene is not fused to an additionalring however. The optional substituents on the thiophene ring system mayinclude alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, heteroaryl,halogen, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl,CF₃, cyano, amino, alkylamino, and aryl. Preferred are alkyl, alkoxy,CF₃ and halo. The preferred number of substituents is 0, 1 or 2,preferably 0 or 1.

In both the preceding embodiments—i.e., wherein Ar¹ is a thiophene ringsystem unfused to another ring or a furanyl ring system, the phenylgroup Ph, of formula 3 is optionally substituted by one or morenoninterfering substituents. Preferably these substituents are alkyl,alkoxy, cycloalkyl, cycloheteroalkyl, heteroaryl, halogen,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, acyl,carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, CF₃,cyano, amino, alkylamino and aryl. Particularly preferred substituentsare alkyl, alkoxy, CF₃ and halo. It is preferred that the number ofsubstituents be 0, 1 or 2, preferably 0 or 1 and more preferably 0.

In a third embodiment of the compounds of formula (3), although Ar¹ canbe any optionally substituted aryl group other than optionallysubstituted indolyl, benzimidazolyl, or benzotriazyl, it is requiredthat at least one of Ar¹ and Ph is substituted by at least onesubstituent comprising a saturated ring system, optionally containing1-2 N atoms or 1-2 O atoms. Preferred such substituents are cyclohexyl,cyclopentyl, piperazinyl, piperidinyl, or morpholinyl. It is preferredthat only one saturated ring system be present as a substituent on Ar¹or Ph. In addition to this required substituent, either or both of Ar¹and Ph may contain additional substituents selected from those set forthin the previous embodiments as substituents on the phenyl (Ph) moiety.Preferred substituents are alkyl, alkoxy, CF₃ and halo.

As set forth above, particularly preferred forms of the compounds offormula (3) are those set forth in FIGS. 1A-1I.

The compounds of formula (1), (2) or (3) may be supplied in the form oftheir pharmaceutically acceptable acid-addition salts including salts ofinorganic acids such as hydrochloric, sulfuric, hydrobromic, orphosphoric acid or salts of organic acids such as acetic, tartaric,succinic, benzoic, salicylic, and the like. If a carboxyl moiety ispresent on the compounds of formula (1), (2) or (3), the compound mayalso be supplied as a salt with a pharmaceutically acceptable cation.

In the event the compounds of formula (1), (2) or (3) contains one ormore chiral centers, all of the stereoisomers are included within thescope of the invention, as well as mixtures thereof. Thus, the compoundsof formula (1), (2) or (3) in these instances may be supplied as asingle stereoisomer, as a racemic mixture, as a partially racemicmixture, or generally, a mixture of stereoisomers in any proportion.

The invention is directed, in addition to methods of treatment and ofpreparing medicaments, to compounds falling within the scope of formula(1), (2) or (3) as compositions of matter.

In one aspect, the invention is directed to compounds of the generalformula (2), and the pharmaceutically acceptable salts thereof, whereinAr¹ is optionally substituted furanyl, thiophenyl, or phenyl systemcontaining 0, 1 or 2 N as heterocyclic atoms or naphthyl systemcontaining 0, 1, 2 or 3 N as heterocyclic atoms, X¹ is CO or an isosterethereof; Y is optionally substituted alkyl (1-6C), optionallysubstituted aryl (6-10C), or optionally substituted arylalkyl (7-11C); nis 1; Z is N or CH; X² is CH₂ or an isostere thereof; and Ph isoptionally substituted phenyl.

The invention is also directed to compounds of formula (2) and thepharmaceutically acceptable salts thereof, wherein Ar¹ is optionallysubstituted furanyl, thiophenyl, or phenyl system containing 1 or 2 Natoms as heterocyclic atoms or naphthyl system containing 0, 1, 2, or 3N atoms as heterocyclic atoms, X¹ is CO or an isostere thereof; Y isoptionally substituted alkyl (1-6C), optionally substituted aryl(6-10C), or optionally substituted arylalkyl (7-11C); n is 0-1; Z is Nor CH; X² is CH₂ or an isostere thereof; and Ph is optionallysubstituted phenyl; wherein said substituents on Ar¹ and Ph areindependently selected from the group consisting of straight or branchedchain alkyl (1-6C), straight or branched chain alkenyl (2-6C), halo,RCO, COOR, CONR₂, SO₂NR₂, —OOCR, —NROCR, —NROCOR, OR, SR, NR₂, NO₂, CN,or CF₃, wherein R is H or straight or branched chain alkyl (1-6C).

The invention is also directed to a compound of the formula (2) and thepharmaceutically acceptable salts thereof, wherein Ar¹ is an orthosubstituted furanyl, thiophenyl, or phenyl system containing 0, 1 or 2 Nas heterocyclic atoms, or naphthyl system containing 0, 1, 2 or 3 N asheterocyclic atoms; said ortho substituent is straight or branched chainalkyl (1-6C), straight or branched chain alkenyl (2-6C), halo, RCO,COOR, CONR₂, SO₂NR₂, —OOCR, —NROCR, —NROCOR, OR, SR, NR₂, NO₂, CN, orCF₃, wherein R is H or straight or branched chain alkyl (1-6C), with theproviso that when said Ar¹ is phenyl and said ortho substituent is OR,either R must be alkyl (3-6C) or Ar¹ must be

where R′ is H, alkyl (1-6C), alkenyl (2-6C) or arylalkyl (7-12C);

X¹ is CO or an isostere thereof; Y is optionally substituted alkyl(1-6C), optionally substituted aryl (6-10C), or optionally substitutedarylalkyl (7-11C); n is 0-1; Z is N or CH; and Ph is optionallysubstituted phenyl.

The ortho position is defined herein as the position in the ringadjacent the X¹ position, for example the 2-position in a 5-memberedring.

Preferred embodiments of the compounds of the invention are as describedabove with respect to compounds useful in the invention methods. Inparticular piperidine forms are preferred over piperazines.

Particularly preferred compounds of the invention include:

1-(2-methoxy-4-hydroxybenzoyl)-4-benzylpiperidine;

1-(2-methoxy-4-methoxybenzoyl)-4-benzylpiperidine;

1-(2-methoxy-4-benzyloxybenzoyl)-4-benzylpiperidine; and

1-(2-methoxy-4-methoxybenzoyl)-4-(4-fluorobenzyl)piperidine.

In addition, the following table illustrates preferred compounds of theinvention.

Compound # Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

In addition to the compounds of formula (2) described above, theinvention is directed to compounds of formula (3) as described above,and in particular the compounds of formula (3) set forth in FIGS. 1A-1I.

All of the compounds of the invention are useful in methods to treatsubjects wherein the subject harbors a condition which is mediated by aninappropriate p38α kinase activity. Such conditions include variousproinflammation conditions and various cardiac indications as describedin the published documents cited above. The compounds of the inventionare thus useful in preparing medicaments for the treatment of theseconditions by admixing the compounds with suitable pharmaceuticallyacceptable excipients. Such excipients are well known in the art and aredescribed in Remington's Pharmaceutical Sciences, latest edition, MackPublishing Co., Easton, Pa., incorporated herein by reference.

The invention is also directed to methods to prepare the compoundsuseful in the invention by forming the carboxamides from the appropriatearoyl compounds as halides or free acids.

Synthesis Methods

Preferably, the compounds useful in the invention are synthesized,generally, by coupling an aroyl moiety to a benzyl-substitutedpiperazine or piperidine. The general approach is shown in ReactionSchemes 1-6 hereinbelow. Reaction Scheme 3 is directed to the particularcircumstance wherein Ar² includes an amino group to be functionalized inthe presence of potentially competing groups.

Administration and Use

The methods of the invention are directed to treating conditionsassociated with p38 kinase activity, for example, inflammatoryconditions. Thus, the compounds of formula (1) or their pharmaceuticallyacceptable salts are used the manufacture of a medicament forprophylactic or therapeutic treatment of mammals, including humans, inrespect of conditions characterized by excessive production of cytokinesand/or inappropriate or unregulated cytokine activity on such cells ascardiomyocytes, cardiofibroblasts and macrophages.

The compounds of formulas (1) and (2) inhibit the production ofcytokines such as TNF, IL-1, IL-6 and IL-8, cytokines that are importantproinflammatory constituents in many different disease states andsyndromes. Thus, inhibition of these cytokines has benefit incontrolling and mitigating many diseases. The compounds of formulas (1)and (2) are shown herein to inhibit a member of the MAP kinase familyvariously called p38 MAPK (or p38), CSBP, or SAPK-2. The activation ofthis protein has been shown to accompany exacerbation of the diseases inresponse to stress caused, for example, by treatment withlipopolysaccharides or cytokines such as TNF and IL-1. Inhibition of p38activity, therefore, is predictive of the ability of a medicament toprovide a beneficial effect in treating diseases such as coronary arterydisease, congestive heart failure, cardiomyopathy, myocarditis,vasculitis, restenosis, such as occurs following coronary angioplasty,atherosclerosis, rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, multiplesclerosis, acute respiratory distress syndrome (ARDS), asthma, chronicobstructive pulmonary disease (COPD), silicosis, pulmonary sarcosis,sepsis, septic shock, endotoxic shock, toxic shock syndrome, heart andbrain failure (stroke) that are characterized by ischemia andreperfusion injury, surgical procedures, such as transplantationprocedures and graft rejections, cardiopulmonary bypass, coronary arterybypass graft, CNS injuries, including open and closed head trauma,inflammatory eye conditions such as conjunctivitis and uveitis, acuterenal failure, glomerulonephritis, inflammatory bowel diseases, such asCrohn's disease or ulcerative colitis, graft vs host disease, boneresorption diseases like osteoporosis, type II diabetes, pyresis,psoriasis, cachexia, viral diseases such as those caused by HIV, CMV,and Herpes, and cerebral malaria.

Within the last several years, p38 has been shown to comprise a group ofMAP kinases designated p38α, p38β, p38γ and p38δ. Jiang, Y. et al. JBiol Chem (1996) 271:17920-17926 first reported characterization of p38βas a 372-amino acid protein closely related to p38α. Kumar, S. et alBiochem Biophys Res Comm (1997) 235:533-538 and Stein, B. et al. J BiolChem (1997) 272:19509-19517 reported a second isoform of p38β, p38β2containing 364 amino acids with 73% identity to p38α. All of thesereports show evidence that p38β is activated by proinflammatorycytokines and environmental stress, although the second reported p38βisoform, p38β2, appears to be preferentially expressed in the CNS, heartand skeletal muscle compared to the more ubiquitous tissue expression ofp38α. Furthermore, activated transcription factor-2 (ATF-2) was observedto be a better substrate for p38β2 than for p38α, thus suggesting thatseparate mechanisms of action may be associated with these forms. Thephysiological role of p38β1 has been called into question by the lattertwo reports since it cannot be found in human tissue and does notexhibit appreciable kinase activity with the substrates of p38α.

The identification of p38γ was reported by Li, Z. et al. Biochem BiophysRes Comm (1996) 228:334-340 and of p38δ by Wang, X., et al., J Biol Chem(1997) 272:23668-23674 and by Kumar, S., et al., Biochem Biophys ResComm (1997) 235:533-538. The data suggest that these two p38 isoforms (γand δ) represent a unique subset of the MAPK family based on theirtissue expression patterns, substrate utilization, response to directand indirect stimuli, and susceptibility to kinase inhibitors.

Various results with regard to response to drugs targeting the p38family as between p38α and either the putative p38β1 or p38β2 or bothwere reported by Jiang, Kumar, and Stein cited above as well as byEyers, P. A. et al. Chem and Biol (1995) 5:321-328. An additional paperby Wang, Y. et al. J Biol Chem (1998)273:2161-2168 suggests thesignificance of such differential effects. As pointed out by Wang, anumber of stimuli, such as myocardial infarction, hypertension, valvulardiseases, viral myocarditis, and dilated cardiomyopathy lead to anincrease in cardiac workload and elevated mechanical stress oncardiomyocytes. These are said to lead to an adaptive hypertrophicresponse which, if not controlled, has decidedly negative consequences.Wang cites previous studies which have shown that in ischemiareperfusion treated hearts, p38 MAPK activities are elevated inassociation with hypertrophy and programmed cell death. Wang shows inthe cited paper that activation of p38β activity results in hypertrophy,whereas activation of p38α activity leads to myocyte apoptosis. Thus,selective inhibition of p38α activity as compared to p38β activity willbe of benefit in treating conditions associated with cardiac failure.These conditions include congestive heart failure, cardiomyopathy,myocarditis, vasculitis, vascular restenosis, valvular disease,conditions associated with cardiopulmonary bypass, coronary arterybypass, grafts and vascular grafts. Further, to the extent that theα-isoform is toxic in other muscle cell types, α-selective inhibitorswould be useful for conditions associated with cachexia attributed toTNF or other conditions such as cancer, infection, or autoimmunedisease.

Thus, the invention is directed to the use of the compounds of formulas(1) and (2) which selectively inhibit the activity of the p38α, isoformfor treating conditions associated with activation of p38α, inparticular those associated with cardiac hypertrophy, ischemia or otherenvironmental stress such as oxidation injury, hyperosmolarity or otheragents or factors that activate p38α kinase, or cardiac failure, forexample, congestive heart failure, cardiomyopathy and myocarditis.

The manner of administration and formulation of the compounds useful inthe invention will depend on the nature of the condition, the severityof the condition, the particular subject to be treated, and thejudgement of the practitioner; formulation will depend on mode ofadministration. As the compounds of formulas (1) and (2) are smallmolecules, they are conveniently administered by oral administration bycompounding them with suitable pharmaceutical excipients so as toprovide tablets, capsules, syrups, and the like. Suitable formulationsfor oral administration may also include minor components such asbuffers, flavoring agents and the like. Typically, the amount of activeingredient in the formulations will be in the range of 5%-95% of thetotal formulation, but wide variation is permitted depending on thecarrier. Suitable carriers include sucrose, pectin, magnesium stearate,lactose, peanut oil, olive oil, water, and the like.

The compounds of formulas (1) and (2) may also be administered throughsuppositories or other transmucosal vehicles. Typically, suchformulations will include excipients that facilitate the passage of thecompound through the mucosa such as pharmaceutically acceptabledetergents.

The compounds may also be administered topically, for topical conditionssuch as psoriasis, or in formulation intended to penetrate the skin.These include lotions, creams, ointments and the like which can beformulated by known methods.

The compounds may also be administered by injection, includingintravenous, intramuscular, subcutaneous or intraperitoneal injection.Typical formulations for such use are liquid formulations in isotonicvehicles such as Hank's solution or Ringer's solution.

Alternative formulations include nasal sprays, liposomal formulations,slow-release formulations, and the like, as are known in the art.

Any suitable formulation may be used. A compendium of art-knownformulations is found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa. Reference to this manualis routine in the art.

The dosages of the compounds of formula (1) will depend on a number offactors which will vary from patient to patient. However, it is believedthat generally, the daily oral dosage will utilize 0.001-100 mg/kg totalbody weight, preferably from 0.01-50 mg/kg and more preferably about0.01 mg/kg-10 mg/kg. The dose regimen will vary, however, depending onthe conditions being treated and the judgment of the practitioner.

The inhibitors of p38 kinase can be used as single therapeutic agents orin combination with other therapeutic agents. Drugs that could beusefully combined with these compounds include natural or syntheticcorticosteroids, particularly prednisone and its derivatives, monoclonalantibodies targeting cells of the immune system, antibodies or solublereceptors or receptor fusion proteins targeting immune or non-immunecytokines, and small molecule inhibitors of cell division, proteinsynthesis, or mRNA transcription or translation, or inhibitors of immunecell differentiation or activation.

As implicated above, although the compounds of formula (1) may be usedin humans, they are also available for veterinary use in treating animalsubjects.

The following examples are intended to illustrate but not to limit theinvention.

EXAMPLE 1 Preparation of 4-Benzylpiperidin-1-yl Benzene Carboxamide(1-Benzoyl-4-Benzyl Piperidine)

This example illustrates Reaction Scheme 1.

To a mixture of 4-benzylpiperidine (0.263 g, 1.5 mM) anddiisopropylethyl-amine (0.53 mL, 3.0 mM) in 10 mL dichloromethane atroom temperature was added benzoyl chloride (0.281 g, 2.0 mM) and thereaction mixture was stirred at room temperature for 20 h. The reactionmixture was poured into water and extracted with ethyl acetate (2×25mL). The combined organic extract was washed with 1 N HCl, water andbrine. The extract was dried over Na₂SO₄ and evaporated. The residue waschromatographed on a column of silica gel with ethyl acetate-hexane (10to 50%, gradient). Evaporation of the desired fractions gave 0.402 g(96%) of the title compound as an oil. ¹H NMR (CDCl₃) δ 7.10-7.40 (m,10H), 4.60-4.70 (m, 1H), 3.70-3.80 (m, 1H), 2.80-2.90 (m, 1H), 2.70-2.80(m, 1H), 2.60 (d, 2H), 1.70-1.80 (m, 1H), 1.50-1.70 (m, 2H), 1.20-1.40(m, 2H). MS (ESI) m/e 279 (M⁺)

EXAMPLE 2 Preparation of 4-Benzylpiperidin-1-yl-(4-Amino)BenzeneCarboxamide (1-(4-Aminobenzoyl)-4-Benzyl Piperidine)

This example illustrates Reaction Scheme 2:

4-Aminobenzoic acid (1.61g, 10 mM) was reacted with EDAC (1.92g, 10 mM)in 40 mL dry DMF for 15 minutes. 4-Benzylpiperidine (1.75g, 10 mM) wasadded followed by DMAP (20 mg, catalyst) and the reaction mixture wasstirred for 20 h. The mixture was poured into water and extracted withmethylene chloride (3×100 mL). The combined extract was washed withdilute hydrochloric acid, saturated sodium bicarbonate and water anddried over MgSO₄. After evaporation of the solvent, the residue waschromatographed with methylene chloride-methanol (0 to 2% methanol,gradient) to yield 1.60 g (50%) of the title compound afterrecrystallization from ether-Hexane. ¹H NMR (CDCl₃): δ 7.40-7.10 (m,7H), 6.70 (d, 2H), 3.95-3.90 (broad m, 2H), 2.85-2.75 (broad m, 2H), 2.6(d, 2H), 1.85-1.80 (m, 1H), 2.75-2.65 (broad m, 2H), 1.15-1.05 (broad m,2H). MS (ESI) m/e 294 (M⁺).

Examples 3 and 4 illustrate Reaction Scheme 3:

EXAMPLE 3 Preparation of 1-(2-Chloro-4-Aminobenzoyl)-4-Benzyl Piperidine

A. Preparation of the BOC-Protected Intermediate

To a solution of 2-Chloro-4-t-butoxycarbonylaminobenzoic acid (0.50 g,1.85 mM) in CH₂Cl₂ (8.0 mL) was added triethylamine (0.37 g, 0.52 mL,3.70 mM) and 4-benzylpiperidine (0.65 g, 0.65 mL, 3.70 mM). This wasfollowed by the dropwise addition of thionyl chloride (0.44 g, 0.27 mL,3.70 mM). The mixture was allowed to stir at room temperature for 1 h,whereupon it was poured into water and extracted with CH₂Cl₂ (3×10 mL).The combined organics were dried over Na₂SO₄ and evaporated. Silica gelchromatography (5% methanol in dichloromethane) afforded 0.30 g (38%) ofBOC-protected intermediate, i.e., 1-(2-chloro-4-t-butoxycarbonylaminobenzoyl)-4-benzyl piperidine. ¹H NMR (CDCl₃): δ 7.30-7.10 (m, 2H),6.60 (s, 1H), 4.70 (m, 1H), 3.30(m, 1H),2.50(d,2H), 1.80(m,2H),1.60(m,2H), 1.50(s,9H), 1.20(m,3H). MS (ESI) m/e 428 (M⁺).

B. 1 -(2-chloro-4-t-butoxycarbonyl aminobenzoyl)-4-benzyl piperidine(0.15 g, 0.35 mM) from paragraph A was added to 4.0 N HCl in dioxane(2.0 mL). The mixture was stirred for 2 hours at room temperaturewhereupon it was triturated with Et₂O. The Et₂O was decanted and theresidue was dried in vacuo to yield 0.10 g (87%) of the title compound.¹H NMR (CDCl₃): 6 7.50 (m, 3H), 7.30 (m, 4H), 7.20 (d, 1H), 7.10 (d,2H), 4.6 (t, 1H), 3.30 (d, 1H), 2.90 (t, 1H), 2.70 (t, 1H), 2.50 (s,2H), 1.70 (d, 2H), 1.60 (t, 1H), 1.20 (broad s, 2H). MS (ESI) m/e 327(M⁺−1).

EXAMPLE 4 Preparation of 1-(2-Chloro-4-Methylaminobenzoyl)-4-BenzylPiperidine

A solution of 1-(2-chloro-4-t-butoxycarbonyl aminobenzoyl)-4-benzylpiperidine (0.88g, 2.06 mM) in THF (4.0 mL) from paragraph A of Example3 was added dropwise to an ice-cooled suspension of NaH in THF (4.0 mL).Stirring was continued for 0.5 hours before adding iodomethane (0.35 g,0.15 mL, 2.47 mM) dropwise. The mixture was then allowed to stir at roomtemperature for 16 hours, at which time it was poured into water andextracted with ethyl acetate (3×10 mL). The combined extracts were driedover Na₂SO₄ and concentrated. The residue was dissolved in 4.0 N HCl indioxane (10.0 mL) and stirred at room temperature for 2 hours whereuponit was triturated with Et₂O. The Et₂O was decanted and the residue wasdried in vacuo to yield 0.56 g (79%) of1-(2-chloro-4-methylaminobenzoyl)-4-benzyl piperidine. ¹H NMR (CDC1₃): δ7.60-7.10 (m, 8H), 4.70 (t, 1H), 3.40 (broad s, 1H), 3.00 (m, 1H), 2.90(s, 3H), 2.70 (m, 1 H) 2.60 (m, 1H), 1.80 (broad s, 2H), 1.60 (broad s,1H), 1.30 (m, 2H). MS (ESI) m/e 342 (M⁺)

EXAMPLE 5 Preparation of Additional Compounds of Formula (2)

Using the techniques set forth in Examples 1-4, the following additionalcompounds of the invention were prepared:

1-(4-methoxybenzoyl)-4-benzyl piperidine,

1-(4-cyanobenzoyl)-4-benzyl piperidine,

1-(4-phenylbenzoyl)-4-benzyl piperidine,

1-(3-methoxybenzoyl)-4-benzyl piperidine,

1-(3,5-dimethoxybenzoyl)-4-benzyl piperidine,

1-(2-chlorobenzoyl)-4-benzyl piperidine,

1-(2-bromobenzoyl)-4-benzyl piperidine,

1-(2-iodobenzoyl)-4-benzyl piperidine,

1-(2-methoxybenzoyl)-4-benzyl piperidine,

1-(2-methylbenzoyl)-4-benzyl piperidine,

1-(2-phenylbenzoyl)-4-benzyl piperidine,

1-(2-(2-carbomethoxyethen-1-yl)benzoyl)-4-benzyl piperidine,

1-(2-naphthoyl)-4-benzyl piperidine,

1-(1-naphthoyl)-4-benzyl piperidine,

1-(2-furanoyl)-4-benzyl piperidine,

1-(2-thiophenoyl)-4-benzyl piperidine,

1-(2-dimethylaminobenzoyl)-4-benzyl piperidine,

1-(3-dimethylaminobenzoyl)-4-benzyl piperidine,

1-(4-dimethylaminobenzoyl)-4-benzyl piperidine,

1-(3,4,5-trimethoxybenzoyl)-4-benzyl piperidine,

1-(2-acetamidobenzoyl)-4-benzyl piperidine,

1-(3-acetamidobenzoyl)-4-benzyl piperidine,

1-(4-acetamidobenzoyl)-4-benzyl piperidine, and

1-(4-formamidobenzoyl)-4-benzyl piperidine.

EXAMPLE 6 Preparation of1-Phenyl-8-1,3,8-triazaspiro[4.5]Decan-4-One-3-Acetyl-4-Benzylpiperidine

This example illustrates Reaction Scheme 4.

Acid I [J Med Chem (1996), 39(16):3169-3173]: 1.0 g, 2.57 mmol and4-Benzylpiperidine, (0.46 g, 2.6 mmol) were treated with 0.51 g EDAC.HClin 10 mL dichloromethane (DCM) in the presence of 200 μL 0.1M DMAP inDMF. After stirring at room temperature for 4 hours, the reactionmixture was concentrated and the residue was taken up in 50 mL ethylacetate (EtOAc). The EtOAc layer was washed with 10% aqueous sodiumcarbonate, 10% aqueous hydrochloric acid, sodium chloride solution anddried over anhydrous sodium sulfate. Concentration gave crude product asa white solid. This material was chromatographed usingethylacetate/hexane on silica gel to the give Boc-protected compound asa white solid. 700 mg EIMS M⁺ 546. 100 mg of the Boc-protected compoundwas treated with 10 mL 4N HCl in dioxane for 60 mins. The reactionmixture was concentrated and the solid obtained was filtered through asintered glass funnel and washed with hexane. Extensive drying gave thehydrochloride salt of Example 1. EIMS M⁺ 446. 65 mg.

EXAMPLE 7 Preparation of 4-Phenyl-3-Pyrroyl-4-Benzylpiperidine

This example illustrates Reaction Scheme 4.

4-Phenyl-3-pyrrole carboxylic acid (333 mg, 3mole) and4-Benzylpiperidine (525mg 3 mmole) were dissolved in 15 mldichloromethane/dimethylformamide(1.1). EDAC-HCl (573mg, 3 mmole) wasadded and the reaction mixture was stirred overnight. The solvent wasremoved and residue redissolved in EtOAc, the EtOAc was washed with 10%HCl, 0.1 M NaOH, water, the EtOAc extract was dried over magnesiumsulfate (anh). Evaporated EtOAc to obtain 489 mg product.

Unless otherwise indicated all compounds were prepared following themethod outlined above using carboxylic acids that are eithercommercially available or are available by synthesis, using methodsknown in the literature.

EXAMPLE 8 Preparation of (V)4-(4′)-Nitrophenyl-3-Purroyl-4-Benzylpiperidine

This example illustrates Reaction Scheme 6.

Preparation of II: Sodium hydride (614 mg 25.6 mmole) was suspended in40 ml diethyl ether. Methyl 4-nitrophenyl-trans-cinnamate (4.14 g, 20mmole), tosylmethylisocyanate (4.29 g, 22 mole) dissolved in Et2O/DMSO(2:1) 40 ml were added dropwise under nitrogen over 20min period. Themixture was stirred for 1 hour at room temperature. Water was added tothe reaction mixture and precipitate was filtered. The aqueous layer wasextracted with Et2O (2×75 ml), The combined extracts were dried overMgSO4 and solvent removed under reduced pressure to give 1.42 g product.EIMS M⁺ 247.

Preparation of III: Methyl-3-(4-nitrophenyl)-2-pyrrole carboxylate (626mg 2.54 mmole) was treated with potassium hydroxide (713 mg, 12.7 mmole)in methanol/water (50:50). The reaction mixture was refluxed 2.5 hours.Methanol was evaporated, the solution was cooled and acidified withHCl(aq) to pH 7. The mixture was extracted with ethyl acetate, combinedextracts dried over MgSO4(anh.) and concentrated to give 440mg product.EIMS M⁺ 232.

Preparation of IV: 3-(4-nitrophenyl)-2-pyrrole carboxylic acid (440 mg1.89 mmole) and 4-Benzylpiperidine (331 mg 1.89 mmole) were dissolved inDCM/DMF(10:1), EDAC (360 mg, 1.89 mmole) was added and the reactionmixture was stirred for 18 hr at room temperature. The solvent wasevaporated, residue dissolved in EtOAc, washed with 10% HCl, 0.10M NaOH,water, the EtOAc layer was dried over MgSO₄, solvent evaporated to give240 mg product. Product was chromatographed on silica gel with EtOAc:hex(8:2) to give 180mg purified product. EIMS M⁺ 389.

Preparation of (V) 4-(4′)-Nitrophenyl-3-purroyl-4-benzylpiperidine: 180mg of the nitro compound was dissolved in 10 ml methanol, 10% Pd/C (60mg) was added and hydrogenated under hydrogen balloon for 2 hours. Thecatalyst was filtered over celite, solvent was evaporated to give 136mgof the desired product. EIMS M⁺ 359.

EXAMPLE 9 Assay for p38 Kinase Inhibition

The compounds to be tested were solubilized in DMSO and diluted intowater to the desired concentrations. The p38 kinase was diluted to 10μg/ml into a buffer containing 20 mM MOPS, pH 7.0, 25 mM beta-glycerolphosphate, 2 mg/ml gelatin, 0.5 mM EGTA, and 4 mM DTT.

The reaction was carried out by mixing 20 μl test compound with 10 μl ofa substrate cocktail containing 500 μg/ml peptide substrate and 0.2 mMATP (+200 μCi/ml gamma-32P-ATP) in a 4× assay buffer. The reaction wasinitiated by the addition of 10 μl of p38 kinase. Final assay conditionswere 25 mM MOPS, pH 7.0, 26.25 mM beta-glycerol phosphate, 80 mM KCl, 22mM MgCl₂, 3 mM MgSO₄, 1 mg/ml gelatin, 0.625 mM EGTA, 1 mM DTT, 125μg/ml peptide substrate, 50 μM ATP, and 2.5 μg/ml enzyme. After a 40minute incubation at room temperature, the reaction was stopped by theaddition of 10 μl per reaction of 0.25 M phosphoric acid.

A portion of the reaction was spotted onto a disk of P81phosphocellulose paper, the filters were dried for 2 minutes and thenwashed 4× in 75 mM H₃PO₄. The filters were rinsed briefly in 95%ethanol, dried, then placed in scintillation vials with liquidscintillation cocktail.

Alternatively, the substrate is previously biotinylated and theresulting reactions are spotted on SAM^(2TM) streptavidin filter squares(Promega). The filters are washed 4× in 2M NaCl, 4× in 2M NaCl with 1%phosphoric acid, 2× in water, and briefly in 95% ethanol. The filtersquares are dried and placed in scintillation vials with liquidscintillation cocktail.

Counts incorporated are determined on a scintillation counter. Relativeenzyme activity is calculated by subtracting background counts (countsmeasured in the absence of enzyme) from each result, and comparing theresulting counts to those obtained in the absence of inhibitor. IC₅₀values were determined with curve-fitting plots available with commonsoftware packages. Approximate IC₅₀ values were calculated using formula

IC ₅₀ (app)=A×i/(1−A)

where A=fractional activity and i=total inhibitor concentration.

The percent inhibition of p38-α kinase was determined at variousconcentrations in order to determine IC₅₀ values. Table 1 showscompounds tested for the percent inhibition of p38-α kinase atconcentrations of 15 μM, 5 μM, 1 μM and 0.2 μM. The table shows variousembodiments of Ar¹X¹; unless otherwise noted, Ph is unsubstitutedphenyl, Z is CH and n is 0. Thus, all of the compounds in Table 1 are4-benzyl piperidines, unless otherwise noted. All show substantialinhibition at 15 μM, some as high as 99%. Virtually all are inhibitoryat 0.2 μM.

TABLE 1 Comp. No. Ar¹X¹ 1 benzoyl 2 4-methoxybenzoyl 3 4-cyanobenzoyl 44-phenylbenzoyl 5 3-methoxybenzoyl 6 3,5-dimethoxybenzoyl 72-chlorobenzoyl 8 2-bromobenzoyl 9 2-iodobenzoyl 10 2-methoxybenzoyl 112-methylbenzoyl 12 2-(2-carboxymethoxy ethen-1-yl) benzoyl 132-naphthoyl 14 1-naphthoyl 15 2-furanoyl 16 2-thiophenoyl 17 note 1 182-dimethylaminobenzoyl 19 3-dimethylaminobenzoyl 204-dimethylaminobenzoyl 21 2-pyridoyl 22 3-pyridol 23 4-pyridol 24 note 225 3,4,5-trimethoxybenzoyl 26 2-chloro-4-acetamidobenzoyl 272-4-dimethylbenzoyl 28 4-acetamidobenzoyl 29 4-formamidobenzoyl 302-aminobenzoyl 31 3-aminobenzoyl 32 4-aminobenzoyl 334,5-dimethoxybenzoyl 34 2,4-dimethoxybenzoyl 35 2-hydroxybenzoyl 362-benzoxybenzoyl 37 3,5-bis-trifluoromethylbenzoyl 382,6-dimethoxybenzoyl 39 2-methylaminobenzoyl 40 6-quinolyl 412-chloro-4-benzamidoyl 42 2-hydroxy-4-aminobenzoyl 432-chloro-4-aminobenzoyl 44 2-chloro-4-methylaminobenzoyl 452-chloro-4-dimethylaminobenzoyl 46 2-methoxy-4-nitrobenzoyl 472-methoxy-4-aminobenzoyl 48 4-guanidinobenzoyl 49 2-bromobenzoyl (note3) 50 phenylsulfonyl 51 4-amino-3-pyridoyl 52 2-methoxybenzoyl (note 4)Note 1: In compound 17, X¹ is CO and Ar¹ has the structure:

Note 2: In compound 24, X¹ is CO and Ar¹ has the structure:

Note 3: In compound 49, n is 1 and Y is methyl. The methyl and benzylgroup at the 4-position of the piperidine ring are cis to each other.Note 4: In compound 52, Z is N; compound 52 is a piperazine derivative.In some cases, IC₅₀ values have been determined as well as the ratio ofIC₅₀ values for inhibition of β as compared to αp38 kinase. Thecompounds in Table 2 show IC₅₀ of about 200 nM to 1.5 μM. Those testedare specific for p38-α at least by a factor of 5.

TABLE 2 Comp. No. Ar¹X¹ 1 benzoyl 2 4-methoxybenzoyl 5 3-methoxybenzoyl7 2-chlorobenzoyl 8 2-bromobenzoyl 9 2-iodobenzoyl 10 2-methoxybenzoyl11 2-methylbenzoyl 16 2-thiophenoyl 18 2-dimethylaminobenzoyl 193-dimethylaminobenzoyl 20 4-dimethylaminobenzoyl 28 4-acetamidobenzoyl29 4-formamidobenzoyl 32 4-aminobenzoyl 34 2,4-dimethoxybenzoyl 352-hydroxybenzoyl 38 2,6-dimethoxybenzoyl 39 2-methylaminobenzoyl 432-chloro-4-aminobenzoyl 44 2-chloro-4-methylaminobenzoyl 452-chloro-4-dimethylaminobenzoyl 49 2-bromobenzoyl (note 3)

EXAMPLE 10 Preparation of Ortho-Substituted Aroyl Derivatives

The aroyl piperidines or piperazines of formula (2) can be provided withortho-substituents via metallation as described by Beak, P. et al., JOrg Chem (1982) 47:34-46; Bindal, R. D. et al., J Org Chem (1987)52:3181-3185; Gshwend, H. et al., Org Rxns (1979)26:1. The generalprocedure is shown as follows:

The starting material is first metallated with butyl lithium in thepresence of base and then treated with an electrophile to provide theappropriate substitution. The electrophile may be an alkyl group, butadditional functionality may be introduced by appropriate choice of theelectrophile. For example, use of benzaldehyde as the source of theelectrophile results in the secondary alcohol.

Compounds with further substitutions on the aroyl moiety can also beused as substrates, but those that contain an N—H require twoequivalents of the butyl lithium/base.

EXAMPLE 11A Preparation of4-Benzylpiperidin-1-yl-(2-Methoxy-4-Benzyloxy)Benzene Carboxamide

A. Methyl 2-hydroxy-4-benzyloxybenzoate:

To a solution of methyl 2,4-dihydroxybenzoate (17.5 g, 104 mM) inacetone at 0° C. were added potassium carbonate (52.5 g, 350 mM) andbenzyl bromide (13.8 mL, 116 mM). The mixture was stirred at 0° C. for 2h, followed by stirring at RT for 16 h. This mixture was filteredthrough a pad of Celite and concentrated. The resulting material waspartitioned between ethyl acetate and water. The organic layer waswashed with a saturated sodium bicarbonate solution, dried (Na₂SO₄),filtered and concentrated. The residue was purified via silica gelchromatography with ethyl acetate-hexane (1 to 20%, gradient).Evaporation of the desired fractions resulted in 13.48 g (50%) of thetitle compound as a white solid. ¹H-NMR (CDCl₃) δ 7.80 (d, 1H),7.50-7.30 (m, 5H), 6.55 (m, 2H), 5.10 (s, 2H), 3.95 (s, 3H). MS (ESI)m/e 258 (m⁺).

B. Methyl 2-methoxy-4-benzyloxybenzoate:

To an ice-cooled solution of methyl 2-hydroxy-4-benzyloxybenzoate fromparagraph A (12.92 g, 50.1 mM) in DMF (200 mL) was added NaH in a 60%oil dispersion (3.00 g, 75.0 mM). The mixture was stirred for 5 min, atwhich time MeI (7.9 mL, 127 mM) was added dropwise. The mixture wasallowed to stir at RT for 16 h, whereupon it was poured onto ice andextracted with ethyl acetate. The organics were washed with water andbrine, then dried (Na₂SO₄) and concentrated to yield 13.11 g (96.3%) ofthe title compound as a tan solid. ¹H-NMR (CDCl₃) δ 7.85 (d, 1H),7.50-7.30 (m, 5H), 6.55 (m, 2H), 5.15 (s, 2H), 3.95 (s, 3H), 3.90 (s,3H). MS (ESI) m/e 272 (m⁺).

C. Title Compound:

To a solution of 4-benzylpiperidine (27.5 mM, 4.85 mL) in toluene (75mL) at −78° C. was added Me₃Al (2 M solution in hexane, 32.5 mM, 16.25mL). The mixture was stirred at −78° C. for 10 min followed by stirringat RT for 1 h. The mixture was once again cooled to −78° C. and asolution of methyl 2-methoxy-4-benzyloxybenzoate from paragraph B (20.0mM, 6.96 g) in toluene (25 mL) was added dropwise. Stirring wascontinued at −78° C. for 10 min, at which time the mixture was allowedto warm to RT and then refluxed for 16 h. The mixture was then cooledand quenched with water, made basic (pH 12) with 1 M NaOH, and stirredat RT for 0.5 h. The mixture was then extracted with ethyl acetate,washed with brine, dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified via silica gel chromatography with ethylacetate-hexane (10 to 60%). Evaporation of the desired fractionsresulted in 639 mg (74.8%) of the title compound as an oil. ¹H-NMR(CDCl₃) δ 7.60-7.10 (m, 11H), 6.60 (m, 2H), 5.10 (s, 2H), 4.75 (br d,1H), 3.80 (app d, 3H), 3.55 (br d, 1H), 3.00-2.50 (m, 4H), 1.80 (m, 2H),1.60 (m, 1H), 1.30 (m, 1H), 1.10 (m, 1H). MS (ESI) m/e 414 (m⁺).

EXAMPLE 11B Preparation of4-Benzylpiperidin-1-yl-(2-Methoxy-4-Hydroxy)Benzene Carboxamide

A Par hydrogenation vessel was charged with4-benzylpiperidin-1-yl-(2-methoxy-4-benzyloxy)benzene carboxamide fromExample 11A (15.00 g, 36.14 mM), dissolved in MeOH (100 mL), and 5%palladium on carbon (1.2 g). The vessel was flushed, placed under 42 psiof H₂, and shaken for 16 h. The slurry was then filtered through Celiteand concentrated. The crude material was recrystallized from ethylacetate/hexane (1:10) to yield 11.24 g (95.7%) of the title compound asa white solid. ¹H-NMR (CDCl₃) δ 7.40-6.80 (m, 6H), 6.30 (m, 2H),4.75(broadd, 2H), 3.50 (app d, 3H), 3.0-2.50 (m, 4H), 1.75 (m, 2H), 1.55 (m,1H), 1.20 (m, 1H), 1.05 (m, 1H). MS (ESI) m/e 324 (m⁺).

EXAMPLE 12 Effect of Ortho-Substitution

Using the methods set forth in Example 10, 1-benzoyl-4-benzylpiperidineisomers, substituted on the benzoyl substituent at various positions,were tested for their ability to inhibit p38α kinase at 15 μMconcentration. The results are shown in Table 3:

TABLE 3 % Inhibition of p38α kinase at 15 μM ortho meta para F 98 92 94Cl 99 80 85 Br 99 74 96 methyl 98 90 97 CF₃ 98 49 66

As shown in Table 3, for any given substituent, the ortho isomer showsenhanced inhibition.

The IC₅₀ values, obtained as set forth in Example 10, were alsodetermined for the ortho-, meta-, and para-methoxy substituted benzoylforms of 1-benzoyl-4-benzylpiperidine. These results are shown in Table4:

TABLE 4 IC₅₀'s of methoxy analogs IC₅₀ (μM) ortho 0.287 meta 1.1 Para0.605

It is clear from these results that substitution at the ortho positionis preferred.

The molar refraction values for the ortho derivatives containing chloro,bromo and methoxy substituents were determined as a measure of the sizeof the substituent as described by Hansch, C. et al., J Med Chem (1973)16:1207-1216. A linear correlation between the MR values and percentinhibition of p38α at 200 nM concentrations of the compounds wasobtained. The smallest substituent (chloro) showed an MR value of about6 and 52% inhibition at 200 nM; the compound with an intermediate MRvalue of about 8 (methoxy) provided 68% inhibition at thisconcentration, and the compound having the largest substituent (bromo)showed an MR value of approximately 9 and 72% inhibition at thisconcentration. Thus, it appears that the ability to inhibit p38α kinaseis dependent on the size of the ortho substituent. While not intendingto be bound by any theory, applicants believe that the bulkiersubstituents rotate the aroyl moiety out of the plane of the piperidineor piperazine ring.

EXAMPLE 13 Additional Compounds

Additional compounds within the scope of the invention shown in FIGS.1A-1I have been prepared.

What is claimed is:
 1. A method of treating a condition associated with p38α kinase activity in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound that modulates the activity of p38α kinase, wherein said compound is of formula (3):

wherein Ar¹ is a furanyl ring system optionally substituted by noninterfering substituents other than phenyl; X¹ is CO or an isostere thereof; Z is N or CH; X² is CH₂ or an isostere thereof; and Ph is optionally substituted phenyl.
 2. The method of claim 1 wherein X¹ is CO and X² is CH₂.
 3. The method of claim 1 or 2 wherein said furanyl ring system is optionally substituted by one substituent selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, CF₃, cyano, amino and alkylamino.
 4. The method of claim 1 or 2 wherein Ph is optionally substituted by one substituent selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, CF₃, cyano, amino, alkylamino and aryl.
 5. A method of treating a condition associated with p38α kinase activity in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound that modulates the activity of p38α kinase, wherein said compound is of formula (3):

wherein Ar¹ is a thiophene ring system optionally substituted by a noninterfering substituent, and not fused to an additional ring; X¹ is CO or an isostere thereof; Z is N or CH; X² is CH₂ or an isostere thereof, and Ph is optionally substituted phenyl.
 6. The method of claim 5 wherein X¹ is CO and X² is CH₂.
 7. The method of claim 5 or 6 wherein said thiophene ring system is optionally substituted by at least one substituent selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, CF₃, cyano, amino, alkylamino, and aryl.
 8. The method of claim 5 or 6 wherein Ph is optionally substituted by one substituent selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, CF₃, cyano, amino, alkylamino and aryl.
 9. A method of treating a condition associated with p38α kinase activity in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound that modulates the activity of p38α kinase, wherein said compound is of formula (3):

wherein Ar¹ is an optionally substituted aryl group other than optionally substituted indolyl, benzimidazolyl, or benzotriazolyl; X¹ is CO or an isostere thereof; Z is N or CH; X² is CH₂ or an isostere thereof; and Ph represents optionally substituted phenyl wherein at least one of Ar¹ and Ph is substituted by at least one substituent comprising a saturated ring system optionally containing 1-2 N atoms and/or 1-2 O atoms.
 10. The method of claim 9 wherein X¹ is CO and X² is CH₂.
 11. The method of claim 9 or 10 wherein Arm is optionally substituted by at least one substituent selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, CF₃, cyano, amino, alkylamino, and aryl.
 12. The method of claim 9 or 10 wherein Ph is optionally substituted by one substituent selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, CF₃, cyano, amino, alkylamino and aryl. 